A5056258649- Click Chemistry and Applications
- Chemical Synthesis and Analysis
- Advanced biosensing and bioanalysis techniques
- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- CRISPR and Genetic Engineering
- Microbial Natural Products and Biosynthesis
- FOXO transcription factor regulation
- Peptidase Inhibition and Analysis
- DNA and Nucleic Acid Chemistry
- Signaling Pathways in Disease
- Genomics and Chromatin Dynamics
- RNA and protein synthesis mechanisms
Scripps Research Institute
2024
Scripps (United States)
2022-2024
Scripps Institution of Oceanography
2022-2024
Summary Chemical proteomics enables the global assessment of small molecule-protein interactions in native biological systems and has emerged as a versatile approach for ligand discovery. The range molecules explored by chemical has, however, been limited. Here, we describe diversity-oriented synthesis (DOS)-inspired library stereochemically-defined compounds bearing diazirine alkyne units UV light-induced covalent modification click chemistry enrichment interacting proteins, respectively....
Pioneer transcription factors (TFs) exhibit a specialized ability to bind and open closed chromatin, facilitating engagement by other regulatory involved in gene activation or repression. Chemical probes are lacking for pioneer TFs, which has hindered their mechanistic investigation cells. Here, we report the chemical proteomic discovery of electrophilic small molecules that stereoselectively site-specifically TF, FOXA1, at cysteine (C258) within forkhead DNA-binding domain. We show these...
More than half of the ∼20,000 protein-encoding human genes have at least one paralog. Chemical proteomics has uncovered many electrophile-sensitive cysteines that are exclusive to a subset paralogous proteins. Here, we explore whether such covalent compound-cysteine interactions can be used discover ligandable pockets in paralogs lack cysteine. Leveraging ligandability C109 cyclin CCNE2, mutated corresponding residue paralog CCNE1 cysteine (N112C) and found through activity-based protein...
ABSTRACT Chemical probes are lacking for most human proteins. Covalent chemistry represents an attractive strategy expanding the ligandability of proteome, and chemical proteomics has revealed numerous electrophile-reactive cysteines on diverse Determining which these covalent binding events impact protein function, however, remains challenging. Here, we describe a base-editing to infer functionality by quantifying their missense mutation cell proliferation. We show that resulting atlas,...
Summary Most human proteins lack chemical probes, and several large-scale generalizable small-molecule binding assays have been introduced to address this problem. How compounds discovered in such “binding-first” affect protein function, nonetheless, often remains unclear. Here, we describe a “function-first” proteomic strategy that uses size exclusion chromatography (SEC) assess the global impact of electrophilic on complexes cells. Integrating SEC data with cysteine-directed activity-based...